Enzyme inhibitors

Abstract

Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers, wherein Ris a carboxylic acid group (—COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; Ris the side chain of a natural or non-natural alpha amino acid; Y is a bond, —C(═O), —S(═O)—, —C(═O)O—, —C(O)NR—, —C(═S)—NR, —C(═NH)NRor —S(═O)NR— wherein Ris hydrogen or optionally substituted C-Calkyl; Lis a divalent radical of formula -(Alk)(Q)(Alk)- wherein m, n and p are independently 0 or 1, Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula —X-Q- or -Q-X— wherein Xis —O—, S— or NR— wherein Ris hydrogen or optionally substituted C-Calkyl, and Qis an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, Alkand Alkindependently represent optionally substituted divalent C-Ccycloalkyl radicals, or optionally substituted straight or branched, C-Calkylene, C-Calkenylene, or C-Calkynylene radicals which may optionally contain or terminate in an ether (—O—), thioether (—S—) or amino (—NR—) link wherein Ris hydrogen or optionally substituted C-Calkyl; Xrepresents a bond; —C(═O); or —S(═O)—; —NRC(═O)—, —C(═O)NR—, —NRC(═O)NR—, —NRS(═O)—, or —S(═O)NR— wherein Rand Rare independently hydrogen or optionally substituted C-Calkyl; z is 0 or 1; A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system wherein the radicals RRNH—Y-L-X-[CH]— and HONHCO-[LINKER]- are attached different ring atoms; and -[Linker]- represents a divalent linker radical linking a ring atom in A with the hydroxamic acid group CONIIOII, the length of the linker radical, from the terminal atom linked to the ring atom of A to the terminal atom linked to the hydroxamic acid group, is equivalent to that of an unbranched saturated hydrocarbon chain of from 3-10 carbon atoms.